Kidney Injury Molecule-1 and the Loss of Kidney Function in Diabetic Nephropathy: A Likely Causal Link in Patients With Type 1 Diabetes

Abstract

OBJECTIVE We evaluated the predictive value and clinical benefit of urinary kidney injury molecule (KIM)-1 for progression of diabetic nephropathy (DN) in type 1 diabetes. We also investigated its causal role for the decrease of estimated glomerular filtration rate (EGFR) by a Mendelian randomization (MR) approach. RESEARCH DESIGN AND METHODS We followed 1,573 patients with type 1 diabetes for 6 years. KIM-1 wasmeasured at baseline and normalized with urinary creatinine. KIM-1 predictive value was evaluated by Cox regression, while its added predictive benefit was evaluated using a panel of statistical indexes. The causality for the loss of renal function was evaluated with MR, utilizing the top signal from our genome-wide association study (GWAS) as the instrumental variable. RESULTS KIM-1 was not an independent predictor of progression of DN when adjusted for albumin excretion rate (AER) and added no prognostic benefit to AER or EGFR. In multiple regressions, KIM-1 was associated with lower EGFR independently of diabetes duration (β =24.066; P < 0.0001) but not of AER. In ourGWAS, rs2036402 in the KIM1 gene was strongly associated with KIM-1 (β = 20.51; P = 6.5 3 10-38). In the MR, KIM-1 was associated with lower EGFR, independently of diabetes duration and AER (β = -5.044; P = 0.040), suggesting a causal relationship. CONCLUSIONS KIM-1 did not predict progression to end-stage renal disease independently of AER and added no prognostic benefit to current biomarkers. Nevertheless, the MR showed that the inverse association of increased KIM-1 levels with lower EGFR is likely to represent a causal link.